反应详情

温度

100 °C

To a solution of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (97.5 mg, 0.208 mmol), trifluoromethanesulfonic acid 1-methylisoquinolin-3-yl ester (62.3 mg, 0.214 mmol), and Pd(PPh3)4 (15 mg, 0.013 mmol) in 1,4-dioxane (3.2 mL, 41 mmol) in a sealable microwave tube was added a solution of Cs2CO3 (135 mg, 0.413 mmol) in H2O (0.95 mL, 53 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 100° C. for 30 minutes. The reaction mixture was diluted with EtOAc, washed with water and brine, and dried over MgSO4. The EtOAc extract was diluted with DCM (to give DCM:EtOAc≈1:1) and filtered through a plug of silica gel. The silica gel was then washed with DCM:EtOAc 1:2, DCM:EtOAc 1:5, and EtOAc until no more product eluted. Filtrate/washings that contained product were concentrated in vacuo. The crude material was chromatographed on silica gel [10 g/70 mL prepacked cartridge, eluting with DCM→DCM:EtOAc 2:1→DCM:EtOAc 1:1→DCM:EtOAc 1:2→EtOAc]. Mixed fractions were combined, concentrated in vacuo, and purified by prep. TLC [20×20 cm plates, 500 μm, eluting with 2% MeOH/DCM (1×) and 4% MeOH/DCM (3×)]. Clean material from prep. TLC was combined with pure fractions from the column chromatography and dried in vacuo, yielding the title compound as viscous, yellow oil. 1H NMR (400 MHz, CDCl3): δ=8.26 (d, J=2.0 Hz, 1H), 8.15 (dd, J=0.8, 8.4 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.88 (s, 1H), 7.77 (d, J=0.4 Hz, 1H), 7.72 (ddd, J=1.2, 7.2, 8.2 Hz, 1H), 7.66 (d, J=0.4 Hz, 1H), 7.62 (ddd, J=1.2, 6.8, 8.2 Hz, 1H), 6.49 (brs, 2H), 4.38-4.20 (m, 3H), 3.03 (s, 3H), 2.92 (brt, J=12.0 Hz, 2H), 2.19 (brd, J=12.0 Hz, 2H), 1.98 (dq, J=4.4, 12.2 Hz, 2H), 1.49 (s, 9H). MS(ES+): m/z=485.18 (100) [MH+], 429.06 (39) [MH+-isobutene]. HPLC: tR=2.76 min (polar—5 min, ZQ3).

1. customThe tube was sealed
2. customevacuated
3. additionrefilled with nitrogen (3×)
4. additionThe reaction mixture was diluted with EtOAc
5. washwashed with water and brine
6. dry with materialdried over MgSO4
7. extractionThe EtOAc extract
8. additionwas diluted with DCM (to give DCM:EtOAc≈1:1)
9. filtrationfiltered through a plug of silica gel
10. washThe silica gel was then washed with DCM:EtOAc 1:2, DCM:EtOAc 1:5, and EtOAc until no more product
11. washeluted
12. concentrationwere concentrated in vacuo
13. customThe crude material was chromatographed on silica gel [10 g/70 mL prepacked cartridge, eluting with DCM→DCM:EtOAc 2:1→DCM:EtOAc 1:1→DCM:EtOAc 1:2→EtOAc]
14. concentrationconcentrated in vacuo
15. custompurified by prep
16. washTLC [20×20 cm plates, 500 μm, eluting with 2% MeOH/DCM (1×) and 4% MeOH/DCM (3×)]
17. customdried in vacuo